This invention relates to a novel method of using an angiotensin II antagonist, such as substituted imidazole compounds, for the treatment of atherosclerosis and/or reducing cholesterol, alone or in conjunction with the treatment of hypertension. The invention also relates to using an angiotensin II antagonist in combination with a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (HMG-Co A reductase inhibitor). The invention also relates to using an angiotensin II antagonist in combination with an HMG-Co A reductase inhibitor and an angiotensin converting enzyme inhibitor. The invention also relates to compositions useful for this method of treatment.
The compounds of this invention are known to inhibit the action of the octapeptide hormone angiotensin II (II) and are useful therefore in alleviating angiotensin induced hypertension. The enzyme renin acts on a blood plasma .alpha..sub.2 -globulin, angiotensinogen, to produce angiotensin I, which is then converted by angiotensin converting-enzyme to AII. The latter substance is a powerful vasopressor agent which has been implicated as a causitive agent for producing high blood pressure in various mammalian species, such as the rat, dog, and man. The angiotensin II antagonist compounds inhibit the action of AII at its receptors on target cells and thus prevent the increase in blood pressure produced by this hormone-receptor interaction. By administering an angiotensin II antagonist compound, such as a compound of formula I, to a species of mammal with atherosclerosis and/or high cholesterol and/or hypertension due to AII, the blood pressure is reduced. The compounds of formula I are also useful for the treatment of high cholesterol by reducing the total cholesterol. Administration of a compound of formula I with a diuretic such as furosemide or hydrochlorothiazide, either as a stepwise combined therapy (diuretic first) or as a physical mixture, enhances the antihypertensives effect of the compound, while also treating atherosclerosis and reducing cholesterol levels. Administration of an angiotensin II receptor antagonist, such as a compound of formula I, with an HMG-Co A reductase inhibitor, such as the compounds of formula II, either as a stepwise combined therapy or as a physical mixture, may enhance the treatment of atherosclerosis and/or the reduction cholesterol levels, while also treating hypertension.
K. Matsumura, et. al., in U.S. Pat. No. 4,207,324 issued Jun. 10, 1980, discloses 1,2-disubstituted-4-haloimidazole-5-acetic acid derivatives of the formula: ##STR2## Wherein R.sup.1 is hydrogen, nitro or amino; R.sup.2 is phenyl, furyl or thienyl optionally substituted by halogen, lower alkyl, lower alkoxy or di-lower alkylamino; R.sup.3 is hydrogen or lower alkyl and X is halogen; and their physiologically acceptable salts. These compounds have diuretic and hypotensive actions.
Furukawa, et al., in U.S. Pat. No. 4,355,040 issued Oct. 19, 1982, discloses hypotensive imidazole-5-acetic acid derivatives having the formula: ##STR3## Wherein R.sup.1 is lower alkyl, cycloalkyl, or phenyl optionally substituted; X.sup.1, X.sup.2, and X.sup.3 are each hydrogen, halogen, nitro, amino, lower alkyl, lower alkoxy, benzyloxy, or hydroxy; Y is halogen and R.sup.2 is hydrogen or lower alkyl; and salts thereof.
Furukawa, et al., in U.S. Pat. No. 4,340,598, issued Jul. 20, 1982, discloses hypotensive imidazole derivatives of the formula: ##STR4## Wherein R.sup.1 is lower alkyl or, phenyl C.sub.1-2 alkyl optionally substituted with halogen or nitro; R.sup.2 is lower alkyl, cycloalkyl or phenyl optionally substituted; one of R.sup.3 and R.sup.4 is --(CH.sub.2).sub.n COR.sup.5 where R.sup.5 is amino, lower alkoxyl or hydroxyl and n is 0, 1, 2 and the other of R.sup.3 and R.sup.4 is hydrogen or halogen; provided that R.sup.1 is lower alkyl or phenethyl when R.sup.3 is hydrogen, n=1 and R.sup.5 is lower alkoxyl or hydroxyl; and salts thereof.
Furukawa, et al., in European Patent Application 103,647 discloses 4-chloro-2-phenylimidazole-5-acetic acid derivatives useful for treating edema and hypertension of the formula: ##STR5## Where R represents lower alkyl and salts thereof.
The metabolism and disposition of hypotensive agent 4-chloro-1-(4-methoxy-3-methylbenzyl)-2-phenyl-imidazole-5-acetic acid is disclosed by H. Torii in Takeda Kenkyushoho, 41, No 3/4, 180-191 (1982).
Frazee, et al., in European Patent Application 125,033-A discloses 1-phenyl(alkyl)-2-(alkyl)-thioimidazole derivatives which are inhibitors of dopamine-.beta.-hydroxylase and are useful as antihypertensives, diuretics and cardiotonics.
European Patent Application 146,228 filed Oct. 16, 1984, by S. S. L. Parhi discloses a process for the preparation of 1-substituted-5-hydroxymethyl-2-mercaptoimidazoles.
A number of references disclose 1-benzyl-imidazoles such as U.S. Pat. Nos. 4,448,781 to Cross and Dickinson (issued May 15, 1984); 4,226,878 to Ilzuka, et al. (issued Oct. 7, 1980); 3,772,315 to Regel, et al. (issued Nov. 13, 1973); 4,379,927 to Vorbruggen, et al. (issued Apr. 12, 1983); amongst others.
Pals, et al., Circulation Research, 29, 673 (1971) describe the introduction of a sarcosine residue in position 1 and alanine in position 8 of the endogenous vasoconstrictor hormone AII to yield an (octa)peptide that blocks the effects of AII on the blood pressure of pithed rats. This analog, [Sar.sup.1, Ala.sup.8 ] AII, initially called "P-113" and subsequently "Saralasin," was found to be one of the most potent competitive antagonists of the actions of AII, although, like most of the so-called peptide-AII-antagonists, it also possesses agonistic actions of its own. Saralasin has been demonstrated to lower arterial pressure in mammals and man when the (elevated) pressure is dependent on circulating AII (Pals et. al., Circulation Research, 29, 673 (1971); Streeten and Anderson, Handbook of Hypertension, Vol. 5, Clinical Pharmacology of Antihypertensive Drugs, A. E. Doyle (Editor), Elsevier Science Publishers B. V., p. 246 (1984)). However, due to its agonistic character, saralasin generally elicits pressor effects when the pressure is not sustained by AII. Being a peptide, the pharmacological effects to saralasin are relatively short-lasting and are only manifest after parenteral administration, oral doses being ineffective. Although the therapeutic uses of peptide AII-blockers, like saralasin, are severely limited due to their oral ineffectiveness and short duration of action, their major utility is as a pharmaceutical standard.
Currently there are several A II antagonists in development. Among these development candidates, is losartan which is disclosed in a U.S. Pat. No. 5,138,069 issued to DuPont on Aug. 11, 1992. Losartan has been demonstrated to be an orally active A II antagonists, selective for the AT.sub.1 receptor subtype.
Some known non-peptide antihypertensive agents act by inhibiting an enzyme, called angiotensin converting enzyme (ACE), which is responsible for conversion of angiotensin I to AII. Such agents are thus referred to as ACE inhibitors, or converting enzyme inhibitors (CEI's). Captopril and enalapril are commercially available CEI's. Based on experimental and clinical evidence, about 40% of hypertensive patients are non-responsive to treatment with CEI's. But when a diuretic such as furosemide or hydrochlorothiazide is given together with a CEI, the blood pressure of the majority of hypertensive patients is effectively normalized. Diuretic treatment converts the non-renin dependent state in regulating blood pressure to a renin-dependent State. Although the imidazoles of this invention act by a different mechanism, i.e., by blocking the AII receptor rather than by inhibiting the angiotensin converting enzyme, both mechanisms involve interference with the renin-angiotensin cascade. A combination of the CEI enalapril maleate and the diruetic hydrochlorothiazide is commercially available under the trademark Vaseretic.RTM. from Merck & Co. Publications which relate to the use of diuretics with CEI's to treat hypertension, in either a diuretic-first, stepwise approach or in physical combination, include Keeton, T. K. and Campbell, W. B., Pharmacol. Rev., 31:81 (1981) and Weinberger, M. H., Medical Clinics N. America, 71:979 (1987). Diuretics have also been administered in combination with saralasin to enhance the antihypertensive effect.
Non-steroidal anti-inflammatory drugs (NSAID's) have been reported to induce renal failure in patients with renal under perfusion and high plasma level of AII. (Dunn, M. J., Hospital Practice, 19:99, 1984). Administration of an AII blocking compound of this invention in combination with an NSAID (either stepwise or in physical combination) can prevent such renal failure. Saralasin has been shown to inhibit the renal vasoconstrictor effect of indomethacin and meclofenamate in dogs (Satoh, et at., Circ. Res. 36/37 (Suppl. I):I-89, 1975; Blasingham, et al., Am J. Physiol. 239:(F360, 1980). The CEI captopril has been demonstrated to reverse the renal vasoconstrictor effect of indomethacin in dogs with non-hypotensive hemorrhage. (Wong, et al., J. Pharmacol. Exp. Ther. 219:104, 1980).